Witchweed, or Striga hermonthica, is a parasitic weed that destroys billions of dollars worth of crops globally every year. It detects its host crops by using strigolactone hormones exuded by the host plant into surrounding soil as a germination stimulant, after which it attaches itself to the root of the host and extracts it nutrients. Several of the key steps of the strigolactone signaling process have been identified, including ligand binding to the receptor, ligand hydrolysis, receptor activation, and association with signaling partners. However, little is known about the exact mechanism of each step. Furthermore, despite high sequence, structure, and ligand binding site conservation across different plant species, one strigolactone receptor in witchweed (ShHTL7) exhibits a picomolar EC50 for downstream signaling, compared to a micromolar EC50 reported in the homologous receptor in Arabidopsis thaliana (AtD14). Previous biochemical and structural studies have hypothesized that this difference in ligand sensitivity can be attributed to a larger binding pocket volume in ShHTL7, resulting in higher binding affinity. Using long timescale molecular dynamics simulations in conjunction with Markov state models, we demonstrate that mutations in several residues outside the binding pocket facilitate a more direct ligand binding pathway in ShHTL7. We also demonstrate that this difference in binding pathway, rather than difference in binding pocket volume, contributes to higher ligand binding affinity compared to AtD14. Finally, free energy profiles of the ligand binding process show that while ShHTL7 does have a higher ligand binding affinity, ligand binding is not primary contributor to the observed difference in EC50 for downstream signaling. This mechanistic study will aid the computational design of selective germination inhibitors for witchweed that have minimal effect on natural signaling processes in host crops.

Divergent ligand binding mechanisms in Arabidopsis thaliana and Striga hermonthica strigolactone receptors

2019 Fall National Meeting

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